1. Technical Field
The present invention is related to the preparation of an oxomorpholinyl dimer and its efficacy as a rescue agent against anthracycline and mitomycin C induced tissue damage. More particularly, the present invention is related to the synthesis of bi(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl) and its use as a protective drug for the prevention or treatment of anthracycline and mitomycin C induced tissue injury.
2. State of the Art
Anthracycline compounds, particularly doxourubicin and daunorubicin, and mitomycin C are useful drugs in the treatment of human malignant diseases. However, the clinical application of these compounds is limited by their tissue or organ toxicity. For instance, tissue necrosis following drug extravasation is a well recognized complication resulting from the intravenous administration of doxorubicin (DOX) or mitomycin C (MIT). The local toxicity is characterized initially by pain, erythema, and swelling at the site of extravasation. The clinical course of tissue damage is variable and indolent, but it can progress to ulcer formation and necrosis of deep subcutaneous structures including tendons, joints, and nerves. Extensive surgical debridement may be required and infection and/or loss of limb function may be secondary complications of this injury.
Of utmost importance in the prevention of drug-induced skin injury is meticulous intravenous technique. However, even when DOX or MIT is administered by experienced and well-trained chemotherapy personnel, the incidence of extravasation may be high. Newer schedules of drug administration, such as weekly dosing or continuous infusion may increase the chance of drug extravasation.
Recommendations for the local treatment of DOX or MIT extravasation are based largely on anecdotal or uncontrolled clinical studies and many agents have been cited as putative antidotes for drug-induced injury. Several animal models have been developed to test the efficacy of these potential antidotes. However, the skin of most of these species differs considerably from human skin and these models have failed to establish a consistently effective pharmacologic treatment for DOX-induced injury. Recently, a swine model was developed to study DOX skin toxicity (Wolgemuth, et al., Proc. Am. Assoc. Cancer Res. 23:171, 1982; Desai, et al., Cancer Treat. Rep. 66:1371-1374, 1982) and only one report has adequately demonstrated predictable and reproducible lesions following intradermal injections of DOX (Okano, et al., Cancer Treat. Rep. 67:1075-1078, 1983). Again, no clear protection against necrosis, by any of 11 agents tested in this model, could be shown, although dimethyl sulfoxide appeared to ameliorate the severity of injury.
Bi(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl) (DHM3) of the present invention represents a class of radical dimer compounds that reacts with DOX in vitro to produce the insoluble and pharmacologically inactive 7-deoxyaglycone metabolite. Various benefits of DMH3 of the present invention are demonstrated.